Podcast: Heart xenotransplants and phage fighting

Host: Benjamin Thompson

Welcome back to the Nature Podcast. This week, we’ll be hearing about the latest advances in heart xenotransplants.

Host: Shamini Bundell

And finding out how soil bacteria fight phages. I’m Shamini Bundell.

Host: Benjamin Thompson

And I’m Benjamin Thompson.

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Host: Benjamin Thompson

First up on the show this week, reporter Noah Baker has been taking the pulse of heart transplants.

Interviewer: Noah Baker

The first human heart transplant was performed in 1967 in Cape Town. This pioneering feat was unfortunately unsuccessful, and the patient died within a few weeks. But as time went on, techniques were improved, outcomes became more favourable. Fast-forward to 1981, and Bruno Reichart carried out Germany’s first successful heart transplant.

Interviewee: Bruno Reichart

That started the renewal of heart transplantation in Germany because everybody thought if such a stupid guy can do it, we can do it as well.

Interviewer: Noah Baker

Bruno went on to do Germany’s first heart-lung transplant, and became the president of the International Federation for Heart and Lung Transplantation.

Interviewee: Bruno Reichart

One of my first patients is still alive I think after 35 or 36 years now.

Interviewer: Noah Baker

Nowadays, more than 5,000 heart transplants are performed every year around the world. But waiting lists are growing and it’s becoming more and more difficult to find donor hearts for those in desperate need.

Interviewee: Bruno Reichart

Well, it’s a story of success. You need more and more organs and the donor pool is the same or if it gets even smaller, especially in Germany, there’s no way in the future that there will be enough hearts to just suffice the needs.

Interviewer: Noah Baker

It’s because of this problem that Bruno became interested in a new type of heart transplant.

Interviewee: Bruno Reichart

I’m involved in the field of xeno-heart transplantation since 1998.

Interviewer: Noah Baker

Xenotransplantation is transplanting an organ from one species into another. In particular, Bruno works with pig hearts and his trials are not using humans, but baboons. Bruno’s hope is than in the future, pig organs could be used for life-saving transplant surgeries.

Interviewee: Bruno Reichart

The heart is only a pump. The muscle contracts, pumps blood. It’s a beautiful, beautiful muscle. No technician can make a machine which lasts for 90 years or so, 80 years. It would just break, fall apart. Nothing will happen when you implant a non-human heart.

Interviewer: Noah Baker

But xenotransplantation is exceedingly complicated. Human immune systems have evolved to reject foreign bodies, and it’s taken decades to overcome these issues for human heart transplantation. Trying to achieve the same when the donor is of a different species, some have said, would be impossible.

Interviewee: Bruno Reichart

It’s actually very difficult and that’s the reason why very smart people say that it’s not possible. The pigs who are on our Earth approximately 90 million years earlier, there’s a difference in the evolution between the animals then and the humans.

Interviewer: Noah Baker

Despite the difficulties, Bruno and his team from Munich have now demonstrated the most successful trials to date – again, not in humans, but in baboons. The transplanted pig hearts kept the baboon subjects alive for more than three times longer than ever before, and this has raised the eyebrows of some others working in the field. Here’s Christoph Knosalla from the German Heart Centre in Berlin, who was not involved in the work.

Interviewee: Christoph Knosalla

I realise that it is really a major step forward in heart xenotransplantation. The group from Munich was able to produce really a sustained survival of more than half a year. Before that, in these life-supporting transplants, the single longest transplant was 57 days.

Interviewer: Noah Baker

In order to achieve this, Bruno and his team pulled together various techniques, some of which have been used by other groups – genetically modifying the pig donors, and applying bespoke immunosuppressession protocols to the baboons. They also needed to stop the hearts growing to their full size – pigs are much larger than baboons, and so a full-sized heart would not fit into the chest cavity and would fail. Additionally, pigs have lower blood pressure than baboons, as they stand on all fours, and so Bruno and his team had to use drugs to thin the baboons’ blood to compensate. And finally, they changed the protocols surrounding the surgery itself. Pig hearts, it seems to Bruno, react differently to human hearts when it comes to transplants.

Interviewee: Bruno Reichart

I think porcine hearts, they look like human hearts, or like primate hearts, but they don’t resist ischemia. Ischemia is a time when the heart is not supplied by oxygen and nutrition, and so they are more vulnerable, and that was a big surprise.

Interviewer: Noah Baker

Bruno used a machine designed by a Swedish group which bathed the donor pig hearts in an oxygenated solution, and before transplant, kept them a bit warmer than in previous attempts at about 8 degrees centigrade. This helped prevent ischemia, which can lead to damage in the heart. Bruno described the surgery.

Interviewee: Bruno Reichart

Then they bring in the porcine heart, and then you do your anastomosis, it’s the left atrium to right atrium, the pulmonary artery, and then you remove the air. It doesn’t bleed because you have done it very meticulously, and you open the clamp and the heart’s getting pink and starts beating. That’s for me amazing.

Interviewer: Noah BakerThe survival of the baboon subjects could be a significant step towards human trials of xenotransplantation, but there’s still a lot of work to be done, and exactly how a human would react is still unclear. Here’s Christoph again.

Christoph Knosalla

Yes, it is not tried in humans. Of course, this is not sure because there are hormone incompatibilities which play a role. So, researchers worldwide, also with other organs, are facing this problem.

Interviewer: Noah Baker

There are also other concerns to overcome, like viruses found in pig DNA, which could possibly be transmitted to humans through transplant. In particular, a family of porcine endogenous retroviruses knows as PERVs. PERVs made the headlines last year, when researchers demonstrated the use of CRISPR to edit PERV genes, but the problem remains to be completely solved. And underlying all of this work, there’s a whole plethora of ethical conversations that need to be had surrounding xenotransplantation. So, a lot of work to look out for in the future. But the science is progressing, so who knows. Perhaps in the near future, you’ll be listening to this podcast reporting the first successful xenotransplantation, and with it, the next step in medical science.

Host: Benjamin Thompson

That was Noah Baker. In his report, you also heard from Bruno Reichart and Cristoph Knosalla. You can read Bruno’s paper and Cristoph’s News and Views article over at nature.com/news.

Host: Shamini Bundell

Later in the show, Nisha Gaind will be joining us with an update on the latest science stories – that’s coming up in the News Chat. Now though, it’s time for the Research Highlights, read this week by Ali Jennings.

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Interviewer: Ali Jennings

Prehistoric people may have been partial to a spot of caviar. Excavations at an ancient campsite, in what is now Germany, yielded pieces of poorly washed pottery that still retained residues of Neolithic carp roe. Researchers wanted to get an idea of exactly what was on the menu, but reconstructing a recipe from remains dating back to roughly 4000 BC, is hardly a piece of cake. To determine the details of the archaic cuisine, the team analysed 6000-year-old proteins that had been burnt onto pieces of prehistoric pot. Some of the proteins they discovered are common in fish eggs, whilst others are found in fish flesh, so the hungry hunter-gatherers may have cooked fish broth in a pot. And microscopic plant remains found round the pot’s rim suggest that they used leaves for a lid. Get a taste of that research over at PLoS One.

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Interviewer: Ali Jennings

Thanks to climate change, the chance of a given region on Earth being both warmer and drier than the historical average is now much higher than it has been in previous years. Predicting the joint occurrence of these kind of climate stresses is hard to do, but a team of Stanford scientists have attempted it, by comparing conditions calculated by climate models to temperatures recorded all the way back to 1931. And what they found was that it’s now twice as likely that during a single year, some places on Earth will experience weather both hotter and drier than the historical average. The research also showed that extreme heat and drought are more likely to affect multiple major agricultural areas in the same year. This suggests that the global supply chain of food could become disrupted. The one potential ray of sunshine is that the we can reduce the risk of such simultaneous events if we successfully cut greenhouse gas emissions in line with the Paris Climate Accord. If you’ve warmed to this story, you can find the research over at Science Advances.

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Interviewer: Shamini Bundell

It’s estimated that there are more bacteria on Earth than there are stars in the Universe, including the many which live in or on the human body. But life isn’t easy in a bacterial world. They have their own invaders, attackers and mortal enemies, in particular, special kinds of bacteria-targeting viruses, known as bacteriophages. In their evolutional battle with these phages, bacteria have developed many weapons, and a paper out in Nature this week has been exploring some new ones. I spoke to author Karen Maxwell and started off asking her why she thinks bacteriophages are such an important area of research.

Interviewee: Karen Maxwell

Bacteriophages are thought to be the most numerous biological entity on Earth, and they play really important roles in controlling bacterial populations in the environment and within the human body.

Interviewer: Shamini Bundell

Does that mean I’m full of bacteriophages right now?

Interviewee: Karen Maxwell

You are full of bacteriophages right now. So, you have about ten times more phages in your body than you have bacterial cells, and we know that they’re playing really important roles in controlling bacterial populations in the human microbiome. So, there have been a number of studies where people have looked at antibiotic delivery and how that affects the bacterial populations in the body and also how it affects the phage populations in the body. There also have been a couple of studies that have come out recently looking at inflammatory bowel diseases like Crohn’s disease and colitis, and so it’s thought that the phage is maybe playing roles that are contributing to these kinds of inflammatory bowel diseases.

Interviewer: Shamini Bundell

So, because we have all these bacteria inside us, either causing infections or the sort of healthy part of our microbiome, there’s this whole complex ecosystem, and if we’re not looking at the bacteriophages as well, then we’re just missing a huge part of the picture.

Interviewee: Karen MaxwellYes, absolutely, and with increasing rates of antibiotic resistance, people are really thinking about using phages for therapies, and there have been a couple of big cases in the US recently where they have successfully used phages as a therapeutic. But I think we need to be keeping in mind that they do carry antibiotic resistance genes, they can carry toxin genes, and so it’s really a double-edged sword.

Interviewer: Shamini Bundell

So, what bacteria were you studying and what’s its ecosystem like? What’s the world like for this bacteria?

Interviewee: Karen MaxwellYeah, so Streptomyces are a kind of bacteria that live in the soil, and they actually are the bacteria that make soil smell like soil. So, there’s other bacteria in the soil that they have to compete against. There are yeast, there are parasites and of course, they are thought to be outnumbered by phages, this viral enemy, by a factor of ten. And it’s well-known that Streptomyces produce a lot of what are known as secondary metabolites. These are small molecules that help them gain a competitive advantage in the soil environment, and it’s estimated that Streptomyces produce on the order of about 100,000 different antimicrobial compounds, and these have been shown to have activity against other bacteria, against fungus and against other parasites that are in the soil. But no one had ever looked to see if they had any activities against phages in the past.

Interviewer: Shamini Bundell

But there are bacterial defence mechanisms against phages that we do know about.

Interviewee: Karen Maxwell

We do, but all of those defence systems are based on proteins, and it really makes sense that bacteria – particularly Streptomyces that produce so many of these small molecules –that they do encode a chemical defence against phage infection.

Interviewer: Shamini Bundell

So, the bacteria are using everything at their disposal – proteins and small chemicals – to fight the phages, and so how did you start investigating these chemical weapons?

Interviewee: Karen Maxwell

I just had graduate students and undergraduate students go out and collect dirt samples from a variety of different places and then we bought the dirt samples back to the lab and we isolated phages from them. And then what we did was we took this collection of phages and we started screening extracts that we made from different Streptomyces strains to see if they had anything in them that could inhibit phage replication. And what we found was that a lot of Streptomyces strains actually produce some kind of compound that protects them from phages.

Interviewer: Shamini Bundell

So, you’ve taken small molecules that have been secreted by Streptomyces, and then tested them against the phages, and out of the ones that did work, was there any kind of pattern that you noticed?

Interviewee: Karen Maxwell

Absolutely, there was. So, what we discovered was that the active compounds that we were discovering are a class of molecules known as DNA intercalators. And so, these molecules actually bind to DNA and prevent it from being transcribed or translated, so prevent the genes from being expressed. And so, Streptomyces are producing these molecules that seem to be preferentially binding to the phage DNA at the concentrations that they’re produced inside the cell, and they prevent the DNA from being able to carry out any of the functions that are required for the phage to survive. But one really interesting thing actually, is that these DNA-intercalating molecules, they actually are fantastic anti-cancer agents and people actually, back in the 1960s, they used phage replication in E. coli as a way to screen for anti-tumour agents, and they discovered a lot of commonly used chemotherapeutics in this manner. But at the time, nobody thought to really think about why are Streptomyces producing anti-cancer agents.

Interviewer: Shamini Bundell

So now that you’ve shown that these molecules are part of the phage defence system, does that provide some new opportunities for using these chemicals?

Interviewee: Karen Maxwell

There’s a lot of interest in trying to find new active molecules, and people are starting to do a lot of screening of different secondary metabolites that are produced by bacteria, and I think this gives us a new way of finding new anti-tumour agents.

Interviewer: Shamini Bundell

And now you have a whole new area of bacterial defence which, if you continue looking at these systems, you could find even more molecules and chemicals which could be medically useful.

Interviewee: Karen Maxwell

Yes, so along with the anti-cancer drugs, of course these could be great to be used as antiviral agents in humans as well for therapeutics.

Interviewer: Shamini Bundell

And what’s your personal next step in exploring this?

Interviewee: Karen Maxwell

So, we are currently exploring the production of other types of small molecules. I’m really interested in discovering the diversity of molecules that actually provide anti-phage resistance. So that’s one area of research, and we are also interested in branching out into other bacteria, so how commonly are these anti-phage compounds produced, and how many different species of bacteria produce them?

Interviewer: Shamini Bundell

That was Karen Maxwell from the University of Toronto, Canada. You can find Karen’s paper at nature.com/nature.

Interviewer: Benjamin Thompson

Finally then on the show, it’s that time where we chat about the news – the News Chat – and I’m joined here in the studio this week by Nisha Gaind, European Bureau Chief here at Nature. Hi Nisha.

Interviewee: Nisha Gaind

Hi Ben.

Interviewer: Benjamin Thompson

So, we’ve got two stories today, Nisha, in the Middle East, and our first story is a conservation story but not maybe sort of conservation in the ecology sense.

Interviewee: Nisha Gaind

Yes, this is a really interesting story about a group of researchers who have gone to Jordan and they’re looking at how conflicts have damaged some of these very important ancient heritage sites in the Middle East.

Interviewer: Benjamin Thompson

And this isn’t using satellite images to get an overall picture of an area, it’s really zooming in on the finer details. Where is this work taking place?

Interviewee: Nisha Gaind

These researchers are actually looking at a site in Jordan called Wadi Rum, and it’s the site of lots of different types of prehistoric settlement, and there’s some beautiful rock art and lots of these have got bullet holes in them. There’s actual physical holes in the rock. So, this team of researchers that is UK-based is trying to see how things like bullet holes impact rock and how this rock is damaged further by weathering processes.

Interviewer: Benjamin Thompson

Right, and how are they doing this then?

Interviewee: Nisha Gaind

So, there are two parts to their research project, and the first bit was the research team going to Jordan and looking at these various paintings and engravings and pieces of archaeological remains, and making some very intricate measurements. So for example, they measured how hard the rocks are, how resistive they are, their permeability, and they looked at these measurements at actual points of impact, so for example, where a bullet might have hit the rock. And then the second part is that researchers in the lab actually sort of simulating this process, so using guns and shooting at different types of rocks, and comparing these two different bits of data to try and estimate how rocks might degrade further.

Interviewer: Benjamin Thompson

Alright, so a little bit CSI then I suppose in the lab, and I guess not all bullets are created equal, I mean what sort of differences have they seen?

Interviewee: Nisha Gaind

So that’s a really interesting thing about this site in Jordan, is that there’s a huge range of different types of bullet impacts. There are older bits of damage from much older types of guns like muskets which had bigger munitions, and damage from much more recent guns like AK-47s that they think has been caused in the past few months. In previous research, the team found that bullets from a .22-calibre gun changed how stone reacted to changes in moisture and temperature, which exacerbated the deterioration.

Interviewer: Benjamin Thompson

You mentioned the team is from the UK, I mean are they working with populations in the local vicinity to aid in their studies or anything like that?

Interviewee: Nisha Gaind

Yes, so this team is led by Lisa Mol who is at the University of West England, and the team has worked with some local experts and also spoken to lots of local residents to see what their views are about this bullet damage, and there are some really interesting opinions. For example, some residents say that they don’t want bullet holes to be repaired and that they should stand as a warning against vandalism or the conflicts that caused them.

Interviewer: Benjamin Thompson

Right, well what about this work Nisha? It’s early but where does it lead?

Interviewee: Nisha Gaind

So ultimately, the team wants to develop some guidelines for people who are on the ground and that might be in Jordan or anywhere in the world where these heritage sites exist. And they want people to record and communicate damage that they might see to these ancient site, and use that information to work out how to conserve them.

Interviewer: Benjamin Thompson

Okay, well let’s move on to our second story today, Nisha, and we’re going to go to Iran, where some people are getting a bit of a sinking feeling.

Interviewee: Nisha Gaind

Yes, Tehran is sinking. The Iranian capital is experiencing some of the highest rates of subsidence in the world.

Interviewer: Benjamin Thompson

And are we talking visible levels of sinking?

Interviewee: Nisha Gaind

Yeah, this is pretty visible. So, what we have here is some new research from satellite images that show the extent of Tehran’s sinking, and in some places, it’s as much as 25 centimetres a year.

Interviewer: Benjamin Thompson

Right, I mean I’m holding an imaginary sort of 30-centimetre ruler. That is not an insignificant amount. I mean how is this happening?

Interviewee: Nisha Gaind

There are lots of different things to contribute to this phenomenon sinking or subsidence, and one of them is sheer population. Tehran is the biggest city in Western Asia. There are about 13 million people, and as urban sprawl spreads, it means that there are increased pressures on ground water and oil and gas and other resources, and it all encourages this sinking.

Interviewer: Benjamin Thompson

Well what does this mean then for the people living in Tehran right now?

Interviewee: Nisha Gaind

So this study, which is going to be published in a journal called Remote Sensing of Environment, pretty much puts data on a problem that is very visible in Tehran. Huge fissures, some of them which are several kilometres in length and a couple of metres wide, are opening up in the southeast of Tehran, and there are also just visible cracks in streets, shifted curbs, cracks in walls and tilting buildings. And as well as all of that, we hear a story from a farmer who fell into a six-metre-deep crack, and these cracks are actually pretty serious for farmers because they drain irrigation water and they leave their ground really parched.

Interviewer: Benjamin Thompson

I mean this isn’t sounding good at all Nisha, but is there anything that can be done to sort of reverse this or to stop it getting any worse?

Interviewee: Nisha Gaind

So, the answer to that is pretty bleak according to this study, and it’s that authorities are fighting a losing battle here as they try to regulate water extraction. A lot of the sinking that has already happened is thought to be irreversible.

Interviewer: Benjamin Thompson

Well, very concerning and certainly something to keep an eye on. Nisha, thank you very much for joining us and listeners, if you’d like more of the latest science news, head over to nature.com/news.

Host: Shamini Bundell

That’s it for this week’s show. We’ll be with another edition of the Nature Podcast next week. But before we go, there’s just time to remind you about our sister podcasts from Scientific American. You can catch them on over at scientificamerican.com/podcasts, or wherever you find your shows. I’m Shamini Bundell.

Host: Benjamin Thompson

And I’m Benjamin Thompson. See you next time.